This is a renewal of the protocol entitled "Children of Bipolar Parents: A High-Risk Follow-up Study" (NIMH #60952) also known as the Bipolar Offspring Study (BIOS). In line with the current NIMH Strategic Plan, BIOS has been investigating the additive effects of behavioral, affective, circadian/sleep, genetic, and psychosocial factors associated with the development of mood disorders in the offspring of parents with bipolar disorder (BP). Enrollment of BIOS sample was completed in July 2007 with 862 children recruited (509 from parents with BP and 353 from community control parents) and a retention rate of 87%. Interviewers, blind to parental diagnosis, assessed offspring every other year with a comprehensive battery of instruments. BIOS is beginning to elucidate a specific developmental progression to bipolarity in the offspring of parents with BP and as to date, offspring of parents with BP are at significantly higher risk to develop BP-I (OR: 19.5) or subsyndromal BP (OR: 31.2). Since most of the sample will enter the age of highest risk to develop BP and other mood disorders during the next funding period, we are proposing to continue to study this sample for 5 more years. For a subset of 200 children of parents with BP and control parents, we propose to measure neurocognitive functioning and activity in, and functional and anatomic connectivity between, neural regions implicated in the pathogenesis of BP, and obtain more precise measurements of puberty using salivary hormonal levels. We hypothesize that, relative to offspring of control parents, offspring of parents with BP will develop over follow-up: 1) higher rates of mood disorders and psychopathology (e.g., mood lability, disrupted sleep) and 2) deficits in neurocognitive functioning and neurocircuitry associated with emotion processing and regulation. In addition, in offspring of parents with BP, onset of BP or any mood disorder will be predicted by the combined effects of development, demographic factors, other psychiatric disorders, dimensional behavioral and mood phenotypes, family environmental factors, and their interactions. Within the subset of offspring of parents with BP who will have neurocognitive and neuroimaging data, onset of BP or any mood disorder will be predicted by abnormal neurocognitive functioning and activity and connectivity in neural circuitry for emotion processing and regulation, that in turn will be associated with sleep and circadian factors, puberty, and clinical and demographic risk factors identified above. Findings from this large study will help identify the initial symptoms and neurobiomarkers related to increased risk of BP in youth. Such findings will facilitate prompt diagnosis and interventions, thus preventing, or at least ameliorating, the negative effects of this severe illness in youth. PUBLIC HEALTH RELEVANCE: Bipolar disorder is a severe illness associated with considerable negative consequences for the normal development of the child and increased risk for suicide and substance abuse. However, little is known about the initial symptoms and the progression of this illness from childhood and adolescence to adulthood. The findings from this large study will help to identify the initial symptoms and some brain biological markers related to the increased risk to develop bipolar in youth. Such findings will advance the field so that prompt diagnosis and interventions are made, thus preventing or at least ameliorating the negative effects of this severe illness in youth.